Strict glycemic control reduces the occurrence of microvascular complications of diabetes at the cost of a three-fold increase in the frequency of severe hypoglycemia. Euglycemic levels are restored by hormonal and neural counter-regulatory mechanisms at the expense of enhance rates of substrate mobilization and rates of glucose production. Our studies have demonstrates that insulin-induced hypoglycemia is also associated with enhanced rates of whole body proteolysis and amino acid oxidation, as well as a significant enhancement in gut protein breakdown. This response, in its majority, is controlled by CNS glucopenia. Our studies suggest that sites responsible for controlling protein and amino acid metabolism during hypoglycemia are most likely located in the hind brain. The general hypothesis of the present proposal is that the "CNS-Gut" axis plays a pivotal role in mobilization of amino acids and proteins during the catabolic response to stress. The studies designed will be performed in the chronically catheterized conscious dog and will investigate the contribution of forebrain and hindbrain neuroglucopenia to triggering the proteolytic responses. In addition, the studies proposed will use surgical and pharmacological interventions to investigate the involvement of direct extrinsic innervation of the "gut" as well as sympathetic, parasympathetic and serotoninergic contribution to modulation the proteolytic responses. The associated hormonal and glucoregulatory responses as well as the contribution of the gut-derived amino acids to enhanced rates of hepatic gluconeogenic amino acid utilization will be assessed using a combination of isotopic and AV difference techniques. Complimentary studies in a rodent model of hypoglycemia to be performed in the final stages of this proposal will be aimed at defining the contribution of specific brain region glucopenia to the proteolytic responses to hypoglycemia. Furthermore, they will determine the specific neurotransmitter alterations that are associated with hypoglycemia. The results from these studies responses to hypoglycemia. These findings will contribute to the understanding of CNS modulation of the peripheral protein and amino acid alterations that are an integral part of the metabolic response to stress.